Is there a difference between clinical angina and experimentally inducible angina? A placebo-controlled experiment in stable coronary artery disease

Context:
Patients often experience chest pain when the heart is short of blood flow due to a narrowing in an artery. We call this symptom 'angina'. We can treat angina with tablets; but sometimes this is not enough, and so doctors open up the narrowing with a metal stent (angioplasty).

Unfortunately, some patients still have pains even after this. Perhaps the pain was not caused by the narrowing after all?

Cardiologists can test whether a narrowing is restricting blood flow and therefore should have angioplasty. However, there is currently no test to say that a patient's pain is actually caused by the narrowing rather than something else. As a result, cardiologists cannot tell whether angioplasty will alleviate the pain or not. This is an important problem because angioplasty cannot genuinely relieve pain that was not caused by the narrowing, yet such angioplasties still carry risks and cost the NHS tens of millions of pounds per year.

Objectives:
The principal aim is to test whether we can identify which patients have chest pain that is truly caused by a narrowed artery.

In 65 patients who have been referred for angioplasty I will:

1. Describe the pattern of chest pain before and after angioplasty.
Patients will record the site, nature and severity of each episode of chest pain they experience for 1 month before and 1 month after angioplasty. They will record these episodes on a smartphone application. In this way, we will know how effective the procedure was and which pains were relieved with angioplasty.

2. Test whether the pain is actually caused by a narrowed artery.
During a normal angioplasty, a miniature balloon is inflated to expand the metal stent. This balloon inflation temporarily blocks blood flow and often causes pain. We will conduct several such balloon inflations to intentionally restrict blood flow and ask the patient to describe their pain in real time. Presumably, if the patient's angina was really caused by the narrowed artery, then blocking the artery should recreate the pain. However, if the narrowed artery was not the cause of their pain, any pain they feel during the experiment would be different in nature. A unique feature of my experiment is that it will be blinded, which means sometimes we really will block the artery and other times it will only be pretend (placebo). The pain should come with the real episodes and not the pretend ones.

3. Test whether patients with closely matching symptoms have a better response to angioplasty.
If this test, of intentionally blocking the artery, shows a pain closely resembling the patient's usual angina, I speculate that these patients will get a great relief of pain from the angioplasty procedure. In contrast, if this test produces a very different type of pain, I speculate that these patients will not get so much relief from the angioplasty.

Applications and benefits:
More than 500,000 angioplasty procedures are performed each year for the treatment of angina. This is a major cost to our NHS. Angioplasty is technically excellent at opening the artery. But if a patient's symptoms were not in fact caused by the narrowed artery, even brilliant angioplasty cannot relieve their symptoms. We have not studied enough how the nature of symptoms relates to the narrowed artery. This has been a blind spot in cardiology for many years.

My research seeks to resolve this by taking a fresh, personalized, symptom-based approach to angina and angioplasty. If successful, this research could pioneer a new diagnostic test. Such a test could tell us which patients have real angina caused by a narrowed artery, and which patients have chest pain from another source.

With this diagnostic ability, cardiologists could better tailor their treatments; identifying the patients in whom stents could most help symptoms, whilst preventing the unnecessary cost and risk associated with angioplasty in those whose symptoms were caused by something else.

Aims:
ORBITA, the first placebo-controlled trial of angioplasty for stable angina, showed a weaker effect than hoped. One interpretation is that we cannot assume that all chest pain reported by a patient, with a coronary stenosis and objective evidence of ischaemia, is in fact angina.

My principal aim is to improve patient selection for PCI by applying a novel symptom-based approach: I will determine whether symptoms, induced by confirmed experimental ischaemia can help us select patients who will truly derive benefit from PCI.

Objectives:
1. I will discover the distribution of symptomatic response to low pressure balloon occlusion of the coronary artery.

2. I will discover the degree of match between the presenting clinical symptom and the symptom elicited by experimental balloon occlusion of the coronary artery (against placebo occlusion).

3. I will test the hypothesis that the degree with which experimentally induced symptoms match the presenting symptom of angina predicts the degree of symptomatic benefit from PCI.

Methods:
I will assess the symptomatic response to placebo-controlled low-pressure balloon occlusion of the coronary artery prior to PCI in 65 patients.

Symptomatic response to PCI will be assessed by patient reported symptoms via a dedicated smartphone app for 1 month before and after PCI. Regression of ischaemia will be assessed with stress echocardiography and Fractional Flow Reserve.

Opportunities:
Despite 500,000 PCIs per year, cardiologists have not identified an evidence-based method of mapping ischaemia to angina in an individual patient. This research may offer a solution to this blind spot.

If successful, this could lay the foundations for a novel direct diagnostic test, not for ischaemia, but for angina of ischaemic origin. Symptom-based personalisation of therapy for stable angina could maximise the therapeutic efficacy of PCI, helping us better tune the treatments to those most able to benefit from them.

1. Academic beneficiaries
Despite decades of research, deep uncertainties persist regarding the role of PCI for stable coronary disease. By finally tackling the question of how ischaemia translates into clinical angina, this targeted study has the potential for a profound impact on the future of research in this field. Our findings may re-centre the focus away from indiscriminate identification and correction of ischaemia, to a personalised, symptom-centred approach. In this way, we will advance our collective knowledge of stable coronary disease and define the true role for PCI in this setting.

This study will have global reach. Many have commentated that placebo-controlled interventional trials would not be possible in other countries. Performing this research in the UK marks the nation and the MRC out as investors in research excellence and pioneers in experimental methods which lead to real scientific impact.

2. Healthcare policy makers at governmental level
When contemporary guidelines for PCI in stable coronary disease are followed, and PCI is tested against placebo, it is found to be less effective than hoped. This suggests that current guidelines are not optimally selecting patients who will derive symptomatic benefit from PCI. The cost of this inadequacy can only be estimated, but given the volume of PCI performed, it is unequivocally dramatic.

The clear translatable aim of my study is to assess whether placebo-controlled verification of symptoms during induced ischaemia can more accurately predict a positive response to PCI. Should this new approach to patient selection prove successful, a strong case could be made for revision of these guidelines, resulting in improved effectiveness of our public services and ultimately improved health of our population. Our research group is experienced working with policy makers and has previously successfully lobbied the European Society of Cardiology to change their guidance on peri-operative beta blockade.

3. Commercial Exploitation
The ultimate goal of this research is to develop a novel direct diagnostic test, not for ischaemia, but for angina of ischaemic origin. Given the vast patient population that this test would potentially serve, the prospect would be exceptionally attractive to industry. This group has first-hand experience of pioneering novel diagnostic tests and driving them through commercial realisation. The proposed supervisors were pivotal in the development of the instantaneous wave-free ratio (iFR) which has been commercialised by Philips Volcano and has been endorsed with a class 1A recommendation. I will draw on this experience, engage industry early and aim for similar success in this venture. The Imperial Innovations Group is available to offer advice with regards patents and licencing.

4. Deliver highly trained researchers
Through hands-on training delivered by world class supervisors, I am confident that this fellowship, at this institution, with this project, will deliver me as a highly skilled academic cardiologist. I aim to emerge as a young leader in advanced coronary haemodynamics and placebo controlled invasive study. I will use this period as a catalyst for my academic career, focussing on the acquisition of the skills and attributes which will allow me to make a lifetime of impact in cardiology.

5. Promoting placebo-control invasive experimentation to the wider research community
Blinding is essential to avoid bias when symptomatic endpoints are used to assess interventional procedures. This fact is not specific to cardiovascular research but has long been overlooked by the academic community. We will, for the first time, assess placebo-controlled symptoms during invasive study, setting a new standard for future studies in this area. We will make our methods and blinding protocol publicly available to encourage other academics, across all disciplines to engage in this bias resistant methodology.